This invention relates to a method for the treatment and/or prevention of urinary incontinence usually in women during the post menopausal period or during pregnancy or postpartum with a nitric oxide synthase substrate (e.g., L-arginine), a nitric oxide donor or both, alone or in combination with estrogen and/or progestin (e.g., hormone replacement therapy (HRT)), or with supplementation with alpha-adrenergic agonists, beta-adrenergic receptor blocking agents, cholinergic-receptor-blocking compounds and/or cholinergic-receptor-stimulating drugs.
Women in industrialized nations can now expect to spend over a third of their lives in the postmenopausal period. One of the major problems women face during the climacteric period is urinary incontinence. Urinary incontinence is also a problem during pregnancy or postpartum. In pregnancy, this condition may be related to altered steroid and nitric oxide levels rather than the physical presence and pressure of the growing fetus.
Urinary incontinence is the inability of the bladder to retain urine resulting in urine loss as a consequence of either urge (urge incontinence), or physical or mental stress (stress incontinence). There have been many studies of the effects of estrogen and progesterone therapy for incontinence (Barbieri, 1994; Sartori et al., 1995). These studies indicate that estrogen and/or progesterone replacement therapy can partially alleviate incontinence in some women (Elia and Bergman, 1993; Sartori et al, 1995). However, there is no conclusive evidence that hormone therapy alone is sufficient to cure incontinence (Cardozo and Kelleher, 1995). Some studies have shown that hormone replacement therapy helps prevent postmenopausal recurrent urinary tract infections and improves urinary incontinence (Cardozo and Kelleher, 1994). Other studies suggest hormone supplementation with alpha-adrenergic agonists, beta-adrenergic-receptor blocking agents, cholinergic-receptor-blocking compounds and cholinergic-receptor-stimulating drugs (Barbieri, 9194; Brandeis and Resnick, 1992).
The normal bladder fills at a physiological rate dictated by the function of the kidneys and the bladder can accommodate large volumes of urine. This phenomenon has been attributed to physical properties of the bladder as well as a neural inhibitory system. The inhibitory mechanism may involve inhibition of parasympathetic activity or an increase in sympathetic tone to produce detrusor relaxation and allow filling to occur. During filling the outlet neck of the bladder and urethra are contracted preventing leakage. Voiding or micturition is characterized by a-relaxation of the outlet neck and the urethra followed by contraction of the detrusor muscle. The process begins again when the bladder is empty and the detrusor relaxes and the outlet neck and urethra contract to seal off the bladder and maintain continence.
It is now well known that HRT (hormone replacement therapy), such as estrogen treatment, improves or reverses the adverse effects of the decrease of sex steroid secretion by the ovaries during menopause. Estrogens have also been shown to improve mood and psychological well-being in postmenopausal women and they also prevent atrophic changes in the urogenital tract. Estrogens have been shown to effect arterial tone and this may help to explain the reduction in hot flushes observed in postmenopausal women with estrogen therapy. On the other hand, unopposed estrogen therapy has been associated with endometrial hyperplasia and endometrial cancer. Many studies have shown that the addition of progesterone to estrogen HRT decreases the risk of endometrial cancer and even reverses endometrial hyperplasia. However, progestins are not without their own untoward side effects. Progestins may reinforce the beneficial effects of estrogens on the cardiovascular system. Modern HRT now employs combinations of an estrogen and a progestin as in the general case for most contraceptives.
One of the most exciting recent advances in biology and medicine is the discovery that nitric oxide is produced by endothelial cells and that it is involved in the regulation of vascular tone, platelet aggregation, neurotransmission and immune activation (Furchgott and Zawadzki, 1980; Moncada, Palmer and Higgs, 1991; Ignarro, 1991). Nitric oxide is an important mediator of relaxation of the muscular smooth muscle (Montada, Palmer and Higgs, 1991) and was formerly known as EDRF (endothelin-derived relaxing factor) (Furchgott and Zawadzki, 1980; Moncada, Palmer and Higgs, 1991). Nitric oxide is synthesized by the oxidative deamination of a guanidino nitrogen of L-arginine by at least three different isoforms of a flavin-containing enzyme, nitric oxide synthase (Montada, Palmer and Higgs, 1991). Synthesis of nitric oxide has been shown to be competitively inhibited by analogues of L-arginine; NG-nitro-L-arginine methyl ester (L-NAME), NG-monoethyl-L-arginine (LMMA), N-iminoethyl-L-ornithine (L-NIO), L-monomethyl-L-arginine (L-NNMA) and L-NG-methylarginine (LNMA) and Nw-nitro-L-arginine (L-NA).
Nitric oxide elevates levels of cGMP (1,4,5-cyclic guanosine monophosphate) within the vascular smooth muscle to produce relaxation and to reduce blood vessels tone (Moncada, Palmer and Higgs, 1991). Nitric oxide binds to heme and thus activates soluble guanylate cyclase (Ignarro, 1991) to increase the cellular content of cGMP. It has long been recognized that nitrovasodilators, such as nitro-prusside and nitroglycerin, inhibit vascular smooth muscle contractility to produce relaxation or to reduce vascular tone. These agents have been used since the late 1980s as vasodilators. However, only recently has the mechanism of action of these compounds been realized. Nitrovasodilators are now classified as nitric oxide donors because they are metabolized or spontaneously release nitric oxide (Moncada, Palmer and Higgs, 1991). The long-used nitrovasodilators may be regarded as substitution therapy for a failing physiological mechanism. Nitric oxide is also produced by macrophages and other immune cells.
There is a substantial body of evidence from animal experiments that a deficiency in nitric oxide contributes to the pathogenesis of a number of diseases, including hypertension, atherosclerosis and diabetes (Montada, Palmer and Higgs, 1991). There are many recent studies showing that the inhibition of nitric oxide synthase dramatically increases blood pressure.
Nitric oxide may also be involved in accommodation of the bladder during filling or relaxation of the bladder neck and urethra during voiding. The bladder is innervated by nonadrenergic and noncholinergic nerves (NANC nerves) and nitric oxide is thought to be a neurotransmitter in these types of nerves (Ehren et al, 1994; Andersson and Persson, 1994; Smet, et al, 1994; Lee et al., 1994). There is evidence showing that nitric oxide containing nerves are localized to a greater extent in the outlet region and urethra compared to the detrusor (Andersson and Persson, 1994; Lee et al., 1994). However, whether nitric oxide is involved in voiding by relaxing the urethra and bladder neck or in bladder filling by relaxing the detrusor is unclear. There have been few studies of the effects of nitric oxide donors on either the urethra, bladder neck or detrusor muscle.